1. Field of the Disclosure
The disclosure relates generally to methods and small molecules that can be used to inhibit phosphate transport. Particularly, the disclosure is directed to methods and small molecules that can be used to treat or prevent diseases that are related to disorders in the maintenance of normal serum phosphate levels. More particularly, this disclosure is directed to methods and small molecules that can be used to treat or prevent hyperphosphatemia.
2. Brief Description of Related Technology
Phosphorus and inorganic phosphate (Pi) participate in numerous critical biological processes including cell signaling, nucleic acid synthesis, energy metabolism, membrane function, and bone mineralization. Thus, significant changes in serum Pi levels or an offset Pi balance can have significant physiological consequences. Rapid decreases in serum Pi concentrations can be manifested in a number of pathologies including myopathy, cardiac dysfunction, abnormal neutrophil function, platelet dysfunction, and red-cell membrane fragility. Chronic serum Pi deficiency can cause impairment in bone mineralization, which can lead to osteomalacia and rickets. In contrast, elevated serum Pi concentrations contribute to the pathogenesis of secondary hyperparathyroidism in patients with chronic renal failure. Hyperphosphatemia and the consequent increase in calcium-phosphate (Ca×P) product results in the calcification of soft tissues and blood vessel walls, and is associated with a higher risk of mortality.
The plasma level of Pi is established mainly through: (1) the control of Pi absorption in the small intestine, which is directly stimulated by vitamin D, (2) factors controlling the rate of bone resorption, and (3) Pi excretion in the kidney, which is under the influence of the parathyroid hormone (PTH) and phosphaturic factors such as fibroblast growth factor-23 (FGF-23). Disturbances of signal pathways controlling phosphate homeostasis, such as inadequate renal function or hypoparathyroidism, often give rise to hyperphosphatemia. Chronic hyperphosphatemia can lead to severe abnormalities in calcium and phosphorus metabolism, which is often manifested by hyperparathyroidism, bone disease and ectopic calcification in joints, lungs, eyes and vasculature. For patients who exhibit renal insufficiency, an elevation of serum phosphorus within the normal range has been associated with the progression of renal failure and an increased risk of cardiovascular events. Conversely, reducing phosphate retention can slow the progression of kidney disease. Thus, for renal failure patients who are hyperphosphatemic and for chronic kidney disease (CKD) patients whose serum phosphate is within the normal range or is only slightly elevated, therapeutic approaches to reduce phosphate uptake and retention are beneficial.
As chronic kidney disease progresses, serum phosphate levels become more difficult to control. More than 60% of patients on hemodialysis were reported to have serum phosphate levels exceeding 5.5 mg/dL. A normal physiological serum phosphorus concentration is generally considered to be between about 2.5 mg/dl to about 4.5 mg/dl (Block G & Port F, Am. J. Kidhey Dis. 2000, 35:1226-1237). Furthermore, hemodialysis patients with serum phosphorus levels greater than 6.5 mg/dL were reported to have a 27% higher mortality risk than patients with serum phosphorus between 2.4 and 6.5 mg/dL. Based on these findings, the National Kidney Foundation—Kidney Disease Outcome Quality Initiative (KJDOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease have recently recommended more stringent actions for controlling serum phosphorus and Ca×P product in order to improve patients' quality of life and longevity.
Current therapeutic approaches to manage hyperphosphatemia include limiting dietary phosphorus intake and employing phosphate binding matrices, both of which are largely inadequate and often poorly tolerated. Early clinical emphasis was directed toward limiting dietary phosphorus intake. Dietary phosphorus comes from three major sources, the inherent phosphorus content in foodstuff, phosphate-containing additives for preservation, and phosphate-containing dietary supplements. Because dietary phosphorus is mainly derived from protein, significant restriction of phosphorus inevitably limits protein intake. As a result, dialysis patients experience an increased risk of malnutrition and mortality.
Phosphate binding matrices initially used were aluminum and calcium compounds. Calcium salts that have been utilized for phosphate binding include calcium carbonate, acetate (such as PhosLo® calcium acetate tablets), citrate, alginate, and ketoacid salts. The advantages of using calcium as the primary phosphate complexing substance are inhibitory effects on parathyroid hormone secretion, low cost, and good tolerability. However, this class of therapeutics generally results in hypercalcemia because such binders can raise the Ca×P index, leading to the manifestations of elevated phosphorus. Aluminum and magnesium salts are available as non-calcium-based phosphate binders, but these compounds have a number of potentially severe side effects. Prolonged used of aluminum gels leads to accumulations of aluminum, and often to aluminum toxicity, accompanied by such symptoms as encephalopathy, osteomalacia, and myopathy.
Polymeric resins, initially developed as bile acid sequestrants, are also being studied or used clinically as Pi binders. Reduced progression or even improvement of vascular calcifications was demonstrated with the use of these polymer-based phosphate binders. However, inherent in their ability to bind cholesterol, these binders also complex and therefore deplete vitamin D, among other important vitamins and nutrients. Lanthanum chloride, a non-calcium-based phosphate binder has also been clinically investigated. The effect on phosphate levels appears to be similar to those of polymer-based phosphate binders. Iron-oxide, because of its ability to complex phosphate is also being used in the clinic. All of the current therapies are based on the complexing of dietary phosphate to make it inaccessible for cross-luminal transport into serum.
For the foregoing reasons, there remains a need for new methods and pharmaceutical compositions to reduce phosphate absorption in the GI tract and to prevent or to attenuate hyperphosphatemia.